New occupational risk factors for chronic renal failure.

Occupational pollutants may have a role in development of chronic renal failure (CRF). Most epidemiological studies have been cross-sectional, limited to certain renal diagnoses, or concentrated on early transient renal effects. In a case-control study, we examined the association between CRF and occupational exposure. Occupational histories of 272 men and women with CRF (of all types) were compared with those of 272 controls matched for age, sex, and region of residence. Exposures were assessed and degree and frequency were scored independently by three industrial hygienists unaware of case/control status. Significantly increased risks of CRF were found for exposure to lead (odds ratio 2.11 [95% CI 1.23-4.36]), copper (2.54 [1.16-5.53]), chromium (2.77 [1.21-6.33]), tin (3.72 [1.22-11.3]), mercury (5.13 [1.02-25.7]), welding fumes (2.06 [1.05-4.04]), silicon-containing compounds (2.51 [1.37-4.60]), grain dust (2.96 [1.24-7.04]), and oxygenated hydrocarbons (5.45 [1.84-16.2]). The frequencies of various occupational exposures were high among patients with diabetic nephropathy. This epidemiological study confirms previously identified risk factors and suggests that additional occupational exposures, for which there is some other experimental evidence, may be important in the development of CRF. The role of grain dust and the association between occupational exposure and diabetic nephropathy merit further investigation.

Wegener granulomatosis is associated to exposure to silicon compounds: a case-control study.

Wegener granulomatosis is a rare disease of unknown aetiology. In the majority of these patients the kidney is involved in the disease process. We performed a case-control study to evaluate the role of occupational exposure in the development of Wegener granulomatosis with renal involvement. The occupational histories of 16 cases with clearly established diagnosis of Wegener granulomatosis with renal involvement were compared with those of 32 age- and sex-matched controls. It was observed that inhalation of silicon-containing compounds such as silica and grain dust gave a nearly sevenfold risk for Wegener granulomatosis. Further epidemiological and experimental work needs to be performed in order to corroborate these findings.

Experimental human exposure to ethylene glycol monomethyl ether.

The uptake of EGME and the urinary excretion of its major metabolite (MAA) was studied in seven male volunteers during experimental exposure to EGME at rest. The exposure concentration was set at 16 mg/m3, the present Threshold Limit Value. A high retention (0.76) remained unchanged during the 4-h exposure period. In combination with a constant pulmonary ventilation and a fixed exposure concentration this resulted in an uptake rate that showed no significant variation in time. The total amount of EGME inhaled corresponded to a dose of only 0.25 mg/kg. During and up to 120 h after the start of the exposure, MAA was detected in the urine. The elimination half-life was on average 77.1 h. The total amount of MAA excreted was calculated by extrapolation and averaged 85.5% of the inhaled EGME. The pharmacokinetic data are compared with those obtained from other human exposure studies to ethylene glycol ethers (EGEE and EGBE).

An improved method for the determination in urine of alkoxyacetic acids.

A sensitive and specific method for the determination in urine of alkoxyacetic acids, the metabolites of ethylene glycol monoalkyl ethers, was developed by combining the advantages of two previously described methods. The acids were determined gas chromatographically as their pentafluorobenzylesters. The alkylation with pentafluorobenzylbromide was performed after dissolving the dry residue of lyophilized urine in methanol. Quantitative derivatization was obtained when the urinary pH was adjusted to pH 7.0, when the reagent concentration was 5% v/v, and when the reaction mixture was heated at 90 degrees C for 3 h. Sample clean-up was performed by adding bidistilled water and the esters were extracted with methylene chloride with high yields (95%). Alkoxyacetic acid concentrations in the range of 0.1 to 200 mg/l could be determined with an average imprecision of +/- 3.5%.

Comparative urinary excretion of ethoxyacetic acid in man and rat after single low doses of ethylene glycol monoethyl ether.

Male rats were given a single oral dose of ethylene glycol monoethyl ether (EGEE), the dose ranging from plausible human exposures (0.5-1 mg/kg) to doses reported in the literature (100 mg/kg). Urinary excretion of ethoxyacetic acid (EAA) and its glycine conjugate was followed up to 60 h after dosing and compared to data of experimentally exposed human volunteers. In rats, the mean elimination half-life of free as well as conjugated EAA was 7.2 h for all doses. EAA was excreted partly as a glycine conjugate (on average 27%), the extent of conjugation being independent of the dose. The conjugation with glycine showed a clearly diurnal variation, the lowest extent being found during the night. The relative amount of EGEE recovered in urine as EAA was only 13.4% for the lowest dose, but increased as the administered dose of EGEE was higher, indicating that EGEE was metabolised at least in two parallel pathways of which one pathway becomes saturated at relatively low doses. In man, urinary excretion of EAA for equivalent low doses of EGEE differed from that in the rat by a longer elimination half-life (mean 42 h), by the absence of EAA conjugates and by a higher recovery.

Survey of ethylene glycol ether exposures in Belgian industries and workshops.

From 1983 onward, 2654 air samples from 336 different plants from the northern part of Belgium were analyzed for the presence of ethylene glycol ethers. One or more ethylene glycol ethers were detected in 262 air samples (9.9%) covering 78 plants or small establishments (23.2%) from a wide variety of industries. Ethylene glycol ethers were mainly present in establishments or operations where printing pastes, inks, paints and varnishes were used. About one third of the air samples covered various other industries. Car repair shops took a major part of this group. It was not always clear, however, in what precise operation the glycol ethers were involved. The ethylene glycol ethers most frequently identified were ethylene glycol monoethyl ether (EGEE) and its acetate (EGEE-Ac). Furthermore, ethylene glycol monomethyl ether (EGME), its acetate (EGME-Ac), and ethylene glycol monobutyl ether (EGBE) also were present in a large number of air samples. The glycol ethers were not distributed equally among the various groups of operations. Most exposure levels were far below the respective Threshold Limit Value (TLVs) (approximately less than 0.5 x TLV). About 25% of ethylene glycol concentrations, however, were higher than the current TLV. Most of the excursions were slight to moderate, although in selected cases extremely high concentrations were recorded. The majority of air samples revealed complex mixtures of ethylene glycol ethers with other solvents, the glycol ethers often being minor components. The possible implication of these other solvents on glycol ether toxicity and metabolism is discussed.

Ethoxyacetic acid: a metabolite of ethylene glycol monoethyl ether acetate in man.

Urinary excretion of ethoxyacetic acid during and after exposure to ethylene glycol monoethyl ether acetate (EGEE-Ac) was followed up in ten healthy male volunteers. During exposure to EGEE-Ac, ethoxyacetic acid levels appeared with a half life of 2.3 +/- 0.1 h. Ethoxyacetic acid excretion continued to increase after exposure was discontinued reaching maximal levels three to four hours later. The decline afterwards could generally be described assuming a half life of 23.6 +/- 1.8 h. A second maximum excretion of ethoxyacetic acid, however, was noticed about three hours after the first. Redistribution of EGEE-Ac or ethoxyacetic acid, or both, from a peripheral compartment to the central compartment could explain this observation. Ethoxyacetic acid excretion increased with an increase in the uptake of EGEE-Ac due to higher exposure concentrations or pulmonary ventilation rate during physical exercise. On average 22.2 +/- 0.9% of the absorbed EGEE-Ac was recovered within 42 hours. Recovery did not change with a higher intake of EGEE-Ac. At any time after the exposure, quantitative relations between ethoxyacetic acid excretion rate and absorbed dose of EGEE-Ac were found. Monitoring ethoxyacetic acid excretion may therefore be used as a measure of a single exposure to EGEE-Ac.

Field study of the urinary excretion of ethoxyacetic acid during repeated daily exposure to the ethyl ether of ethylene glycol and the ethyl ether of ethylene glycol acetate.

The urinary excretion of ethoxyacetic acid (EAA) was studied in a group of five women daily exposed to the ethyl ether of ethylene glycol (EGEE) and the ethyl ether of ethylene glycol acetate (EGEE-Ac) during 5 d of normal production and 7 d after a 12-d production stop. The mean combined exposure concentration of EGEE and EGEE-Ac (expressed in equivalent weight of EGEE) was 14.0 mg/m3 with occasional slight excursions above the current Belgian occupational exposure limit. The daily combined exposure profiles for EGEE and EGEE-Ac were rather constant during the first observation period, but they tended to decrease during the last week. The urinary EAA excretion clearly increased during the work week. Over the weekends the elimination was far from complete, and even after a prolonged nonexposure period of 12 d traces of the metabolite were still detectable. Based on the observations from the first period, a good linear correlation (r = 0.92) was found between the average exposure over 5 d (14.4 mg/m3) and the EAA excretion at the end of the week (105.7 mg/g creatinine). An EAA estimate of 150 +/- 35 mg/g was found to correspond with repeated 5-d full-shift exposures to the respective occupational exposure limit of EGEE (19 mg/m3) or EGEE-Ac (27 mg/m3).

Pulmonary absorption and elimination of ethylene glycol monoethyl ether acetate in man.

Ten male volunteers were exposed to ethylene glycol monoethyl ether acetate (EGEE-Ac) under various conditions of exposure and physical workload. As exposure proceeded, retention, atmospheric clearance, and uptake rate declined slowly to reach steady state levels after three to four hours. Retention increased as a consequence of higher exposure concentrations and of physical workload performed during exposure. Uptake rate was higher as exposure concentration or pulmonary ventilation rate, or both, increased. Subject related factors such as pulmonary ventilation, cardiac output, height, and body fat content also determined individual uptake. During exposure, partial respiratory elimination of EGEE was observed. This finding confirms the hypothesis that EGEE-Ac is first converted to EGEE by (plasma) esterases. The amount of EGEE eliminated at steady state levels correlated more with uptake rate of EGEE-Ac than with exposure concentration. Respiratory elimination of unmetabolised EGEE-Ac accounted for less than or equal to 0.5% of total body uptake. The elimination curves were biexponential indicating that at least two pharmacological compartments are involved. Postexposure breath concentrations were higher as total body uptake increased. Several observations may indicate that the hydrolysis of the ester moiety of EGEE-Ac is hindered by the presence of the natural esterase substrates. With increasing plasma concentrations, however, EGEE-Ac competed more favourably for the available esterase.

Gas chromatographic determination of methoxyacetic and ethoxyacetic acid in urine.

Methoxyacetic acid (MAA) and ethoxyacetic acid (EAA), the major metabolites of, respectively, ethylene glycol monomethyl ether and ethylene glycol monoethyl ether and their acetates, are determined by gas chromatography after extraction from urine and methylation using 2-furoic acid (2-FA) as an internal standard. The mean recoveries (n = 30) from urine of MAA, EAA, and 2-FA are 31.4 +/- 7.0%, 62.5 +/- 13.4%, and 58.4 +/- 8.7%, respectively. The recoveries decreased (p less than 0.001), however, as the total amount of acids increased. Standard curves for MAA and EAA in urine are presented. The detection limits of MAA and EAA are 0.15 and 0.07 mg/l. Intra-assay variation for MAA and EAA was 6.0 +/- 2.5% and 6.4 +/- 2.8% and inter-assay variation was 6.2 +/- 2.2% and 8.9 +/- 2.4%. When volunteers were exposed to air containing ethylene glycol monoethyl ether (20 mg/m3), urinary concentration of EAA rose significantly one hour after the exposure period (2.39 +/- 1.03 v less than or equal to 0.07 mg/l, t = 5.2, p less than 0.005).

Experimental human exposure to n-Hexane. Study of the respiratory uptake and elimination, and of n-Hexane concentrations in peripheral venous blood.

The respiratory uptake rate of n-hexane showed considerable differences in six healthy male persons, exposed at rest to 360 mg/m3 and 720 mg/m3 of n-hexane in inspired air and to 360 mg/m3 under different levels of physical exercise. These differences could partly be explained by a positive correlation with the amount of body fat. At rest also a strong influence of the respiratory minute volume and respiratory frequency on the uptake rate could be proven. The average uptake rate remained virtually constant over a range of 20 to 60 W of continuous external physical load, indicating that under these circumstances the inspired n-hexane concentration alone predominantly determines the uptake rate. The respiratory elimination during the first hours after an exposure was also subject to important inter- and intraindividual fluctuations. The pulmonary ventilation rate at the moment of breath sampling had a pronounced influence on the measured exhaled concentration. On the other hand, there was no apparent effect of the amount of body fat. Generally, the correlation between the amount of n-hexane taken up and breath concentrations at different time intervals was rather poor. n-Hexane concentrations in peripheral venous blood reacted rapidly to changes in exposure conditions, but not in the same proportion as the uptake rate. The blood concentration proved more closely related to respiratory n-hexane retention than to the uptake rate, reflecting the state of saturation of different body tissues. At rest this parameter was clearly influenced by the amount of body fat. A decrease in relative blood perfusion of fatty tissue could explain why such relation was not found during exposure combined with physical effort.